Ruxolitinib for Symptom Control in Patients with Chronic Lymphocytic Leukaemia: a Single- Group, Phase 2 Trial
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UC Irvine UC Irvine Previously Published Works Title Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single- group, phase 2 trial. Permalink https://escholarship.org/uc/item/1180x27h Journal The Lancet. Haematology, 4(2) ISSN 2352-3026 Authors Jain, Preetesh Keating, Michael Renner, Sarah et al. Publication Date 2017-02-01 DOI 10.1016/s2352-3026(16)30194-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Lancet Haematol Manuscript Author . Author Manuscript Author manuscript; available in PMC 2018 February 01. Published in final edited form as: Lancet Haematol. 2017 February ; 4(2): e67–e74. doi:10.1016/S2352-3026(16)30194-6. Ruxolitinib for symptom control in patients with Chronic Lymphocytic leukemia: A Phase II Trial Preetesh Jain, M.D.,PhD1, Michael Keating, M.D.1,*, Sarah Renner, RN1, Charles Cleeland, PhD2,*, Huang Xuelin, PhD3,*, Graciela Nogueras Gonzalez, M.P.H3, David Harris, PhD1, Ping Li, PhD1, Zhiming Liu, PhD1, Ivo Veletic, PhD1, Uri Rozovski, M.D.1, Nitin Jain, M.D.1, Phillip Thompson, M.D.1, Prithviraj Bose, M.D.1, Courtney DiNardo, M.D.1, Alessandra Ferrajoli, M.D.1,*, Susan O’Brien, M.D.1,*, Jan Burger, M.D.1, William Wierda, M.D.1,*, Srdan Verstovsek, M.D.1,*, Hagop Kantarjian, M.D.1,*, and Zeev Estrov, M.D.1,* 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 2Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, Texas 3Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas Summary Background—Disease-related symptoms impair the quality of life of countless patients with chronic lymphocytic leukemia (CLL) who do not require systemic therapy. Currently available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates Janus kinase (JAK)-2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms of patients with myelofibrosis, we hypothesized that ruxolitinib would improve disease- related symptoms in CLL patients. Methods—Ruxolitinib (10 mg twice daily) was administered to symptomatic CLL patients who did not require systemic therapy for CLL. Scores on the brief fatigue inventory (BFI), CLL module of the MD Anderson symptom inventory (MDASI) and symptom-associated interference in daily activities (interference score; IS), were assessed prior to treatment and after 3 months of treatment. Plasma cytokine/chemokine levels were measured at baseline and at 3 months. This manuscript version is made available under the CC BY-NC-ND 4.0 license. Corresponding Author: Zeev Estrov, MD, Department of Leukemia, Unit 428, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030; phone: 713-794-1675; fax: 713-745-4612; [email protected]. *Authors who are full professors Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Authorship Contributions Z.E. designed the study. C.C. performed preliminary symptom score analysis and provided the symptom scores. S.R. was the study’s research nurse. P.J., U.R., C.C., S.R., and Z.E. contributed to data collection and analysis. H.X., N.G. designed the study’s statistical method and monitoring. H.X., N.G., I.V., and U.R. analyzed the data. D.H., L.P., and Z.L., performed the laboratory experiments. Z.E., M.K., N.J., P.T., P.B., C.D., A.F., S.V., S.O.B., J.B., W.W., and H.K. treated and monitored the patients. P.J. and Z.E. wrote the paper. Conflicts-of-Interest Disclosure: Z.E. receives research support from and serves as a consultant to Incyte Corporation. None of the other authors have any conflicts of interest to disclose. Jain et al. Page 2 Findings—Forty-one CLL patients (25 untreated and 16 previously treated) were enrolled. Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author Thirty-two (78%) of the participants experienced ≥20% reduction in the average BFI score or in the average MDASI score. 59% of the participants had ≥2 units reduction in worst fatigue score in 24 hours as assessed by the BFI. The mean percentage reductions in BFI, MDASI, and IS scores were >42% (p<0.0001). Improvements in the three symptom scores correlated with reductions in levels of IL-6, C-reactive protein, CXCL10, osteopontin, TNF-α, ICAM-1/CD54, VCAM-1/ CD106, and beta-2 microglobulin. Furthermore, treatment with ruxolitinib increased and then decreased lymphocyte counts to baseline levels or lower. Grade 3/4 cytopenias were recorded in three patients. Interpretation—In CLL patients, ruxolitinib significantly improved disease-related symptoms, reduced cytokine and chemokine levels, and increased and then decreased lymphocyte counts, likely through mobilization followed by apoptosis of CLL cells. Further studies aimed at testing the therapeutic efficacy of ruxolitinib in CLL are warranted. Funding—Supported by the Incyte Corp., MD Anderson Cancer Center Support Grant CA016672 and Award Number P01 CA049639 from the National Cancer Institute. Keywords Ruxolitinib; symptoms; fatigue; chronic lymphocytic leukemia; inflammatory cytokines/ chemokines INTRODUCTION A significant number of patients with chronic lymphocytic leukemia (CLL) who do not meet the international working group on CLL (iwCLL) 1 criteria for treatment of CLL experience fatigue and/or other disease-related debilitating symptoms that significantly impair their quality of life (QoL) and bring about severe distress and depression.2–5 Disease-associated symptoms such as fatigue, low-grade fever, night sweats, and weight loss are associated with elevated circulating levels of inflammatory cytokines and/or chemokines. Most symptomatic patients are treated with supportive care measures that provide little clinical benefit. As a consequence, a small fraction of patients with severe QoL impairment are offered systemic therapy for CLL.1. Our group has previously assessed the symptoms of 126 consecutive patients with CLL. The most severe symptoms were fatigue, disturbed sleep, drowsiness, distress, and difficulty remembering. About 70% of patients presented with a significantly abnormal symptom score. 6 Inflammatory cytokines induce disease-related symptoms7 in a variety of neoplastic diseases, 8 including hematologic malignancies such as primary myelofibrosis9,10 and CLL. 11 Elevated levels of TNF- α, IL-1β, IL-6, IL-1RA, and IFN-α were previously reported to significantly correlate with cancer associated fatigue, depression, night sweats. 12 The role of cytokines and chemokines in the initiation, maintenance, and progression of CLL has been the subject of intense research over the past two decades, 13 as elevated plasma cytokine levels10 correlate with unfavorable clinical outcome in patients with CLL. 13 Lancet Haematol. Author manuscript; available in PMC 2018 February 01. Jain et al. Page 3 We recently found that stimulation of the B-cell receptor (BCR) of CLL cells activates the Author ManuscriptAuthor Manuscript Author Manuscript Author Manuscript Author Janus kinase (JAK)-2/signal transducer and activator of transcription (STAT)-3 pathway and that the JAK1/2 inhibitor ruxolitinib inhibits the phosphorylation of JAK2 and STAT3 on tyrosine residues of these cells, inducing their apoptosis. 14 Ruxolitinib is known to reduce the levels and inhibit the effects of a number of cytokines, chemokines, and hematopoietic growth factors, providing significant clinical benefits. In patients with myelofibrosis, ruxolitinib alleviates symptoms, improves QoL, and reduces spleen size and tumor burden. 15 Similarly, ruxolitinib was found to improve symptoms and decrease inflammation biomarkers such as the acute phase reactant C-reactive protein (CRP) in patients with steroid-refractory graft-versushost disease16 or pancreatic cancer. 17 Therefore, we sought to investigate the effect of ruxolitinib on disease-related symptoms in patients with CLL. PATIENTS AND METHODS Patient enrollment and treatment This prospective, single arm, single institution, phase II clinical trial designed to test the effect of ruxolitinib on disease-related symptoms of patients with CLL was approved by The University of Texas MD Anderson Cancer Center institutional review board and supported by Incyte Corporation (clinicaltrials.gov identifier number NCT02131584). All patients in this study were enrolled between 15th September 2014 to 20th September 2015. Informed consent (verbal and written) was obtained in accordance with institutional guidelines and the Declaration of Helsinki. Patients with previously untreated or previously treated CLL that did not require therapeutic intervention according to the iwCLL guidelines1 were eligible. CLL patients with performance status ≤ 2 were eligible. According to the 2008 iwCLL guidelines, active disease should be considered if there is significant fatigue, defined as ECOG performance status 2 or worse and inability to work or perform usual activities). All participants were assessed for disease-related